PROJECT SUMMARY Callous-unemotional (CU) traits predict socially debilitating outcomes including Antisocial Personality Disorder (ASPD) and violent crime in adulthood. Despite significant research, the etiology of CU traits is not well understood. The current project incorporates genetic, physiological, neuroanatomical and self-report measures to investigate the etiology of CU traits within the National Institute of Mental Health's (NIMH) Research Domain Criteria (RDoC). Psychopathic/CU traits have long been proposed to reflect an underlying fear-deficit, and therefore this project focuses on measures corresponding with the acute fear construct within the RDoC matrix. Specifically, the physiological measures of facial eyeblink EMG in response to startle and fear-potentiated startle probes, as well as the neuroanatomical volumetric measures of regions of interest (ROIs; anterior cingulate cortex, orbitofrontal cortex, posterior cingulate cortex and amygdala) will be investigated as potential endophenotypes for CU traits. To be considered a putative endophenotype for CU traits a measure must display three characteristics: 1) association with CU traits, 2) heritability, and 3) genetic covariation with CU traits. While startle and neuroanatomy have been shown to meet the first two criteria, little to no research has investigated the third criteria. We hypothesize that startle response and neuroanatomical ROIs will meet all three criteria for endophenotypes of CU traits. Furthermore, we hypothesize that there are specific developmental periods that are most salient for the genetic and environmental factors influencing the progression of CU traits. We will address these hypotheses through the following Specific Aims: 1) investigate the phenotypic relationship between CU traits and startle, 2) examine the genetic influence on the variation and covariation of CU traits and startle throughout childhood and adolescence, and 3) investigate potential neuroanatomical ROIs associated with CU traits, and the genetic influence on the variation and covariation of ROIs and CU traits. We will accomplish these aims using a large, genetically informative, general population sample of juvenile (ages 9-20) twins (N=1696, 848 twin pairs). Biometrical structural equation modeling (i.e., `twin modeling') will be used to decompose the variance and covariance of CU traits and potential endophenotypes proposed here into latent factors reflecting the effects of 1) additive genetics, 2) unique environment and 3) dominant genetic or shared environment. Additionally, how these influences change over the important developmental period of childhood and adolescence also will be examined. This proposal directly corresponds with the NIMH strategic plan for research, which emphasizes the need for research on 1) defining the mechanisms associated with complex behaviors and 2) determining the developmental trajectories of mental illness. The results from this study have the potential to a) confirm the use of specific measures as endophenotypes in future research on CU traits, and b) inform future developmentally-based intervention strategies.